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1.  Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer 
Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A-α protein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A-α protein.
PMCID: PMC4020536  PMID: 24868239
2.  Retinitis Pigmentosa Reduces the Risk of Proliferative Diabetic Retinopathy: A Nationwide Population-Based Cohort Study 
PLoS ONE  2012;7(9):e45189.
To study the association between retinitis pigmentosa (RP) and the progression of diabetic retinopathy (DR).
Using the Longitudinal Health Insurance Database 2000 of Taiwan, we identified individuals with an initial diagnosis for RP during the period of 1997–2008. A non-RP comparison group, 10-fold frequency matched by sex, age, index year and the year of diabetes diagnosed, were randomly selected from the same database. The occurrence of DR was observed for all subjects until the end of 2009. The Kaplan-Meier curves were used to illustrate the cumulative probability of developing DR for the RP group and comparison groups. The hazard ratio (HR) of DR for the RP group relative to the comparison group was estimated using Cox proportional hazards model after adjusting for potential confounders.
The Kaplan-Meier curves were not statistically significant different between the RP group and the comparison group. However, the RP group had a higher cumulative probability of developing DR during the first six to seven years. The cumulative probability kept increasing and became higher in the comparison group but remained unchanged in the RP group. The HR for the RP patients comparing with the comparison group was 0.96 (95% confidence interval (CI) = 0.43–2.14). Stratified by severity, RP was associated with a non-statistically significant reduced risk of proliferative DR (PDR) (HR = 0.70, 95% CI = 0.16–3.14). The HR for non-proliferative DR (NPDR) was 1.08 (95% CI = 0.40–2.86).
In this study, RP was not statistically significant associated with the incidence of DR.
PMCID: PMC3460977  PMID: 23028838
3.  Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition 
PLoS ONE  2012;7(7):e41831.
mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.
PMCID: PMC3406086  PMID: 22848625
4.  Role of autophagy in cancer prevention 
Macroautophagy (autophagy hereafter) is a catabolic process by which cells degrade intracellular components in lysosomes. This cellular garbage disposal and intracellular recycling provided by autophagy serves to maintain cellular homeostasis by eliminating superfluous or damaged proteins and organelles, and invading microbes, or to provide substrates for energy generation and biosynthesis in stress. Thus, autophagy promotes the health of cells and animals and is critical for development, differentiation and maintenance of cell function and for the host defense against pathogens. Deregulation of autophagy is linked to susceptibility to various disorders including degenerative diseases, metabolic syndrome, aging, infectious diseases and cancer. Autophagic activity emerges as a critical factor in development and progression of diseases that are associated with increased cancer risk as well as in different stages of cancer. Given that cancer is a complex process and autophagy exerts its effect in multiple ways, role of autophagy in tumorigenesis is context-dependent. As a cytoprotective survival pathway, autophagy prevents chronic tissue damage and cell death that can lead to cancer initiation and progression. As such, stimulation or restoration of autophagy may prevent cancer. By contrast, once cancer occurs, cancer cells may utilize autophagy to enhance fitness to survive with altered metabolism and in the hostile tumor microenvironment. In this setting autophagy inhibition would instead become a strategy for therapy of established cancers.
PMCID: PMC3136921  PMID: 21733821
autophagy; metabolism; homeostasis; inflammation; cancer prevention
5.  Correlation between Stratus OCT and GDx VCC in early glaucoma, ocular hypertension and glaucoma suspect eyes☆ 
Journal of Optometry  2012;5(1):24-30.
To study the correlation between Stratus optical coherence tomography (OCT) and scanning laser polarimetry (GDx VCC) in measuring retinal nerve fiber layer (RNFL) thickness in eyes with early glaucoma (EG), ocular hypertension (OH), and glaucoma suspect (GS) in a Taiwan Chinese population.
One eye each of 170 subjects (50 eyes with EG, 32 eyes with OH, 38 eyes with GS and 50 healthy eyes) was included. The RNFL thickness was measured by both technologies and three parameters (average, superior and inferior thickness) were correlated using the Pearson's correlation coefficient (r) in each group. Diagnostic capability of two instruments was evaluated in EG, OH and GS eyes based on the area under the receive operator characteristic (AROC) curve.
In healthy and EG eyes, three RNFL parameters were significantly correlated. In OH eye, there was no significant correlation in three parameters. In GS eye, there was significant correlation in inferior thickness only. For healthy vs EG eye, the best parameter with largest AROC was nerve fiber indicator (0.798) for GDx VCC and average thickness (0.787) for OCT. The diagnostic capability of two techniques is poor in OH (AROC, 0.510–0.645) and GS eyes (AROC, 0.510–0.689).
The RNFL thickness measured by OCT and GDx VCC was well correlated in EG and healthy eyes but poorly correlated in OH and GS eyes. When managing the case with OH or GS eye, we should be cautious in interpreting different imaging data.
PMCID: PMC3861155
Stratus OCT; GDx VCC; Early glaucoma; Ocular hypertension; Glaucoma suspect; Stratus OCT; GDx VCC; Glaucoma temprano; Hipertensión ocular; Sospecha de glaucoma
6.  Evaluating Glaucomatous Retinal Nerve Fiber Damage by GDx VCC Polarimetry in Taiwan Chinese Population 
Journal of Optometry  2010;2(4):197-206.
To study the capability of scanning laser polarimetry with variable corneal compensation (GDx VCC) to detect differences in retinal nerve fiber layer thickness between normal and glaucomatous eyes in a Taiwan Chinese population.
This study included 44 normal eyes and 107 glaucomatous eyes. The glaucomatous eyes were divided into three subgroups on the basis of its visual field defects (early, moderate, severe). Each subject underwent a GDx-VCC exam and visual field testing. The area under the receiver-operating characteristic curve (AROC) of each relevant parameter was used to differentiate normal from each glaucoma subgroup, respectively. The correlation between visual field index and each parameter was evaluated for the eyes in the glaucoma group.
For normal vs. early glaucoma, the parameter with the best AROC was Nerve fiber indicator (NFI) (0.942). For normal vs. moderate glaucoma, the parameter showing the best AROC was NFI (0.985). For normal vs. severe glaucoma, the parameter that had the best AROC was NFI (1.000). For early vs. moderate glaucoma, the parameter with the best AROC was NFI (0.732). For moderate vs. severe, the parameter showing the best AROC was temporal-superior-nasal-inferior-temporal average (0.652). For early vs. severe, the parameter with the best AROC was NFI (0.852).
GDx-VCC-measured parameters may serve as a useful tool to distinguish normal from glaucomatous eyes; in particular, NFI turned out to be the best discriminating parameter.
PMCID: PMC3974306
GDx VCC polarimetry; glaucoma; retinal nerve fiber damage; polarimetría GDx VCC; glaucoma; daño en las fibras nerviosas de la retina
7.  Bcl-2 Modulation to Activate Apoptosis in Prostate Cancer 
Molecular cancer research : MCR  2009;7(9):1487-1496.
Apoptosis resistance is a hallmark of cancer linked to disease progression and treatment resistance, which has led to the development of anticancer therapeutics that restore apoptotic function. Antiapoptotic Bcl-2 is frequently overexpressed in refractory prostate cancer and increased following standard hormonal therapy and chemotherapy; however, the rationally designed Bcl-2 antagonist, ABT-737, has not shown single agent apoptosis-promoting activity against human prostate cancer cell lines. This is likely due to the coordinate expression of antiapoptotic, Bcl-2–related Mcl-1 that is not targeted by ABT-737. We developed a mouse model for prostate cancer in which apoptosis resistance and tumorigenesis were conferred by Bcl-2 expression. Combining ABT-737 with agents that target Mcl-1 sensitized prostate cancer cell lines with an apoptotic block to cell death in vitro. In mice in vivo, ABT-737 showed single agent efficacy in prostate tumor allografts in which tumor cells are under hypoxic stress. In human prostate cancer tissue, examined using a novel tumor explant system designated Tumor Tissue Assessment for Response to Chemotherapy, combination chemotherapy promoted efficient apoptosis. Thus, rational targeting of both the Bcl-2 and Mcl-1 mechanisms of apoptosis resistance may be therapeutically advantageous for advanced prostate cancer.
PMCID: PMC2855683  PMID: 19737977
8.  Autophagy Suppresses Tumorigenesis Through Elimination of p62 
Cell  2009;137(6):1062-1075.
Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulate p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-κB regulation and gene expression and to promote tumorigenesis. Thus defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62 controlling pathways critical for oncogenesis.
PMCID: PMC2802318  PMID: 19524509
autophagy; beclin1; atg5; genomic instability; p62; NF- κB; DNA damage; cancer
9.  Brk Activates Rac1 and Promotes Cell Migration and Invasion by Phosphorylating Paxillin 
Molecular and Cellular Biology  2004;24(24):10558-10572.
Brk (for breast tumor kinase) is a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. Brk was originally identified from a human metastatic breast tumor, and its overexpression is frequently observed in breast cancer and several other cancer types. However, the molecular mechanism by which this kinase participates in tumorigenesis remains poorly characterized. In the present study, we not only identified paxillin as the binding partner and substrate of Brk but also discovered a novel signaling pathway by which Brk mediates epidermal growth factor (EGF)-induced paxillin phosphorylation. We show that EGF stimulation activates the catalytic activity of Brk, which in turn phosphorylates paxillin at Y31 and Y118. These phosphorylation events promote the activation of small GTPase Rac1 via the function of CrkII. Through this pathway, Brk is capable of promoting cell motility and invasion and functions as a mediator of EGF-induced migration and invasion. In accordance with these functional roles, Brk translocates to membrane ruffles, where it colocalizes with paxillin during cell migration. Together, our findings identify novel signaling and biological roles of Brk and indicate the first potential link between Brk and metastatic malignancy.
PMCID: PMC533963  PMID: 15572663

Results 1-9 (9)